The incidence of thyroid cancer is rising at the second fastest rate of all malignancies in the United States and has an increasing tumor-specific mortality annually, making it an important public health problem. The reasons for this increasing incidence and rising death rate are uncertain. The goal of the P-01 application is to address the key issues relating to thyroid cancer predisposition, tumorigenesis, and progression in order to enhance the potential for both early and accurate diagnosis and improve the effectiveness of treatments for progressive disease. Based on extensive preliminary data from our group, we propose to: (1) examine and identify predisposing genes for papillary thyroid cancer, (2) determine the critical changes responsible for the development of follicular thyroid cancer in an inherited form of the disease, Cowden syndrome, using a novel animal model, and translate this into a scheme to enhance preoperative diagnosis of this form of thyroid cancer, (3) evaluate and identify the key mechanisms of thyroid cancer induction and dedifferentiation induced by the RET/PTC 1 oncogene, one of the most common genetic abnormalities in papillary thyroid cancer, using a second novel animal model system, and (4) determine mechanisms that regulate tumor invasion and motility for both follicular and papillary thyroid cancers focusing on the models developed in this P-01, and then test novel agents directed at blocking these pathways. Over the past six years, the Pis of the individual projects, and the leaders of the cores have created an environment to successfully perform this integrated P-01 that is unique for thyroid cancer. This includes a substantial database, integration with pathology, and a record of successful collaborative genetics, laboratory, drug development, and clinical research as evidenced by approximately thirty co-authored publications. Thus, this P-01 represents an integrated Bedside-to-Bench-to-Bedside approach targeting the key clinical issues confronting the diagnosis and management of patients with thyroid cancer.